Hereditary Hemochromatosis Mutation Analysis


Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism resulting in the accumulation of excess iron in a variety of body tissues. HH represents one of the most commonly inherited diseases among individuals of Northern European descent, with a frequency between 1 in 200 and 1 in 400. This indicates an estimated carrier frequency of 1 in 8 to 1 in 10. Hemochromatosis may result in toxic iron deposition, which in turn causes organ failure and can lead to cirrhosis, hepatomas, diabetes, cardiomyopathy, arthritis and hypogonadism. Morbidity and mortality can be decreased by the removal of excess iron through therapeutic phlebotomy, if instituted early in the course of the disease.

The gene responsible for HH is located near the major histocompatability complex (MHC) on human chromosome 6p and has been referred to as HLA-H, currently named HFE. Due to a founder effect, a large percentage (87%) of affected chromosomes carry the same mutation, a G to A alteration (nt 845 of the cDNA), which results in a Cys to Tyr substitution at codon 282. A His to Asp substitution at codon 63 resulting from a C to G mutation (nt 187 of the cDNA) has a less frequent occurrence in HH. This H63D mutation is found frequently in C282Y heterozygotes, however it likely is a polymorphism in linkage disequilibrium with a rare disease causing mutation. Both mutations occur in helix regions of the protein, and it has been suggested that the C282Y mutation prevents the HLA-H (HFE) protein from cell surface expression, whereas the H63D mutation affects the association of the protein with beta-microglobulin and subsequent activity.

OMIM: 235200

Clinical Utility

Detection of hereditary mutations that affect normal iron storage. The test is done on peripheral blood specimens for confirmation of clinical diagnosis, carrier status or presymptomatic testing.


PCR amplification and Sanger sequencing of regions with known hotspots.

Loci Tested

  • HFE c.845G>A; C282Y (rs1800562)
  • HFE c.187C>G; H63D (rs1799945)

Specimen Requirements

Peripheral blood collected in EDTA (purple top) is preferred, 3-10mL.

Turnaround Time

Within 1-2 weeks of receipt



Shipment Must Include

Requisition form
Patient pathology report


  1. Carella, M et al. 1997. Mutation analysis of the HLA-H gene in Italian hemochromatosis patients, Am J Hum Genet, 60: 828-832.
  2. Feder, J et al. 1996. A novel MHC class I gene is mutated in patients with hereditary hemochromatosis, Nat Genet, 13: 399-408.
  3. Martinez, P et al. 1997. Compound heterozygotes for hemochromatosis gene mutation: May they help to understand the pathophysiology of the disease? Blood Cells Mol Dis, 23(13): 269-276.